Ecto-5'-nucleotidase (CD73): an emerging role as prognostic factor in allergic sensitization.

Over the years, the importance of the epithelium in the assessment of allergic sensitization and development of allergic diseases has increased. Sensitization to allergens appears to be influenced by genetic and external environmental factors. However, not all subjects exposed to environmental factors that damage epithelial cells suffer from allergic diseases. On this basis, identifying the signaling pathways that characterize the different phenotypes and endotypes of allergy is of high priority for a successful personalized therapy. Ecto-5'-nucleotidase/CD73 is a membrane-bound enzyme responsible for extracellular adenosine accumulation from AMP derived, in turn, from the hydrolysis of extracellular ATP. Current knowledge suggests that CD73 expression and enzymatic activity at epithelial barriers would be of fundamental importance to control the first defense against allergens, by preserving both physical and immunological epithelial barrier functions. Here, we highlight evidence for a crucial role of CD73 in features of allergic sensitization and the potential of this enzyme as prognostic marker and target of therapeutic intervention.

Signaling Pathways in Inflammation and Its Resolution: New Insights and Therapeutic Challenges.

Tissue inflammation is a dynamic process that develops step by step, in response to an injury, to preserve tissue integrity [...].

Systemic administration of glucocorticoids, cardiovascular complications and mortality in patients hospitalised with COVID-19, SARS, MERS or influenza: A systematic review and meta-analysis of randomised trials.

BACKGROUND: Administration of glucocorticoids might reduce mortality in patients with severe COVID-19 but have adverse cardiometabolic effects. OBJECTIVES: to investigate the effect of systemic administration of glucocorticoids on cardiovascular complications and all-cause mortality in patients hospitalised with respiratory viral infections, including COVID-19, SARS, MERS and influenza. METHODS: We identified randomised trials published prior to July 28th, 2021. The Mantel-Haenszel random effects method and the Hartung and Knapp adjustment were used to obtain pooled estimates of treatment effect with 95% confidence intervals. RESULTS: No randomised trials of glucocorticoids for SARS, MERS or influenza reported relevant outcomes. We included eleven COVID-19 randomised trials (8109 patients). Overall, compared to placebo or standard care, glucocorticoids were not associated with a reduction of in-hospital mortality (p = 0.09). In a pre-specified sub-analysis, in-hospital mortality was reduced by 19% when follow-up was restricted to 14 days from randomisation (5/11 trials, 1329 patients, p = 0.02). With longer follow-up (9/11 trials, 7874 patients), administration of glucocorticoids was associated with a trend to benefit for those requiring mechanical ventilation (RR 0.86; 95% CI 0.57-1.27) but possible harm for those not receiving oxygen at randomisation (RR 1.27; 95% CI 1.00 - 1.61), an effect that was significantly different amongst subgroups (p = 0.0359). Glucocorticoids reduced the risk of worsening renal function by 37% (4/11 trials); reported rate of other cardiovascular complications was low. CONCLUSIONS: Administration of systemic glucocorticoids to patients hospitalised with COVID-19 does not lower mortality overall but may reduce it in those requiring respiratory support and increase it in those who do not.

A vitamin E long-chain metabolite and the inspired drug candidate α-amplexichromanol relieve asthma features in an experimental model of allergen sensitization.

Benefits for vitamin E intake in diseases with inflammatory components have been described and related in part, to endogenously formed metabolites (long-chain metabolites, LCM). Here, we have evaluated the role of LCM in relieving asthma features. To this aim, the endogenous vitamin E metabolite α-13'-carboxychromanol (α-T-13'-COOH) that acts as potent 5-lipoxygenase inhibitor has been administered either intraperitoneally or by oral gavage to BALB/c mice sensitized by subcutaneous injection of ovalbumin (OVA). We also have taken advantage of the metabolically stable α-T-13'-COOH derivative α-amplexichromanol (α-AC). Intraperitoneal treatment with α-T-13'-COOH reduced OVA-induced airway hyperreactivity (AHR) as well as peri-bronchial inflammatory cell infiltration. α-AC was more efficacious than α-T-13'-COOH, as demonstrated by better control of AHR and in reducing subepithelial. Both compounds exerted their protective function by reducing pulmonary leukotriene C4 levels. Beneficial effects of α-AC were coupled to inhibition of the sensitization process, as indicated by a reduction of IgE plasma levels, lung mast cell infiltration and Th2 immune response. Metabololipidomics analysis revealed that α-AC raises the pulmonary levels of prostanoids, their degradation products, and 12/15-lipoxygenase metabolites. Following oral administration, the pharmacodynamically different profile in α-T-13'-COOH and α-AC was abrogated as demonstrated by a similar and improved efficacy in controlling asthma features as well as by metabololipidomics analysis. In conclusion, this study highlights a role for LCM and of vitamin E derivatives as pharmacologically active compounds that ameliorate asthmatic features and defines an important role for endogenous vitamin E metabolites in regulating immune response underlying the sensitization process.

Arctium lappa contributes to the management of type 2 diabetes mellitus by regulating glucose homeostasis and improving oxidative stress: A critical review of in vitro and in vivo animal-based studies.

Diabetes is a metabolic disease highly widespread worldwide, and the most common form is the type 2 diabetes mellitus (T2DM). A large number of synthetic drugs are currently available for the treatment of diabetes; however, they present various side effects and, for this reason, people are increasingly inclined to search natural alternative treatments. Among these, Arctium lappa (A. lappa) has interesting anti-diabetic activities, exerted by improving glucose homeostasis and reducing insulin-resistance. In addition, A. lappa exerts a marked antioxidant activity, an effect known to play a pivotal role in the treatment of T2DM. The purpose of this review is to analyse scientific evidence in order to evaluate the role of A. lappa and its bioactive compounds in management of T2DM. The literature search performed provided only in vitro and animal-based studies. No clinical studies have been conducted in order to investigate the effect of A. lappa on T2DM patients. However, available literature provides evidence for further clinical trials in order to confirm these claimed activities on humans.

Devil's claw (Harpagophytum procumbens) and chronic inflammatory diseases: A concise overview on preclinical and clinical data.

Devil's Claw is a traditional medicine that has been long used a wide range of health conditions, including indigestion, fever, allergic reactions, and rheumatism. The main compounds are iridoid glycosides, including harpagoside, harpagide, and procumbide. However, harpagoside is the most responsible for therapeutic activity, and its content is used as reference standard. Here, we analyzed and summarized preclinical and clinical studies focusing on therapeutic efficacy of devil's claw preparations in pathological conditions in which inflammation plays a key causative role.

Polyphenols: A concise overview on the chemistry, occurrence, and human health.

This review gives an updated picture of each class of phenolic compounds and their properties. The most common classification implies the subdivision of phenolics in two main groups: flavonoids (e.g., anthocyanins, flavanols, flavanones, flavonols, flavonones, and isoflavones) and non-flavonoids (e.g., phenolic acids, xanthones, stilbens, lignans, and tannins) polyphenols. The great interest in polyphenols is associated with their high potential application for food preservation and for therapeutic beneficial use. The relationship between polyphenol intake and human health has been exploited with special reference to cardiovascular diseases, hypertension, diabetes, metabolic syndrome, obesity, and cancer. The use of current existing databases of bioactive compounds including polyphenols is described as key tools for human health research.

Adenosine A2A Receptor Agonist, 2-p-(2-Carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine Hydrochloride Hydrate, Inhibits Inflammation and Increases Fibroblast Growth Factor-2 Tissue Expression in Carrageenan-Induced Rat Paw Edema.

Adenosine is the final product of ATP metabolism, mainly derived from the action of 5'-nucleotidase cleavage of AMP. Cellular production of adenosine is greatly enhanced in inflamed tissues, ischemic tissues, and under hypoxia, where ATP is released from damaged cells. Much evidence has been accumulated on adenosine anti-inflammatory effects mediated through A2A receptor activation; A2A adenosine receptor has also been shown to play a role in matrix deposition and wound healing in a damaged tissue, contributing to dermal tissue protection and repair. Fibroblast growth factor-2 (FGF-2) is a powerful mitogen for fibroblast; it is expressed by several inflammatory cell types and plays a pivotal role in angiogenesis, wound healing, gastric ulcer protection. Human recombinant FGF-2 has been shown to have anti-inflammatory effects. The purpose of the present work was to investigate on the anti-inflammatory effect of systemic administration of the adenosine A2A agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride hydrate (CGS21680) in the rat model of carrageenan-induced paw edema. We found that CGS21680 inhibits inflammation induced by carrageenan injection into the rat paw, and this effect is associated to the local reduction of cytokine levels and dermal increase of FGF-2 expression. Our results suggest that FGF-2 might be involved in the anti-inflammatory and tissue protective effect due to A2A receptor activation.

Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases.

Milk thistle (MT; Silybum marianum), a member of the Asteraceae family, is a therapeutic herb with a 2,000-year history of use. MT fruits contain a mixture of flavonolignans collectively known as silymarin, being silybin (also named silibinin) the main component. This article reviews the chemistry of MT, the pharmacokinetics and bioavailability, the pharmacologically relevant actions for liver diseases (e.g., anti-inflammatory, immunomodulating, antifibrotic, antioxidant, and liver-regenerating properties) as well as the clinical potential in patients with alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, drug-induced liver injury, and mushroom poisoning. Overall, literature data suggest that, despite encouraging preclinical data, further well-designed randomized clinical trials are needed to fully substantiate the real value of MT preparations in liver diseases.

Inhibition of CD73 improves B cell-mediated anti-tumor immunity in a mouse model of melanoma.

CD73 is a cell surface enzyme that suppresses T cell-mediated immune responses by producing extracellular adenosine. Growing evidence suggests that targeting CD73 in cancer may be useful for an effective therapeutic outcome. In this study, we demonstrate that administration of a specific CD73 inhibitor, adenosine 5'-(α,ß-methylene)diphosphate (APCP), to melanoma-bearing mice induced a significant tumor regression by promoting the release of Th1- and Th17-associated cytokines in the tumor microenvironment. CD8+ T cells were increased in melanoma tissue of APCP-treated mice. Accordingly, in nude mice APCP failed to reduce tumor growth. Importantly, we observed that after APCP administration, the presence of B cells in the melanoma tissue was greater than that observed in control mice. This was associated with production of IgG2b within the melanoma. Depletion of CD20+ B cells partially blocked the anti-tumor effect of APCP and significantly reduced the production of IgG2b induced by APCP, implying a critical role for B cells in the anti-tumor activity of APCP. Our results also suggest that APCP could influence B cell activity to produce IgG through IL-17A, which significantly increased in the tumor tissue of APCP-treated mice. In support of this, we found that in melanoma-bearing mice receiving anti-IL-17A mAb, the anti-tumor effect of APCP was ablated. This correlated with a reduced capacity of APCP-treated mice to mount an effective immune response against melanoma, as neutralization of this cytokine significantly affected both the CD8+ T cell- and B cell-mediated responses. In conclusion, we demonstrate that both T cells and B cells play a pivotal role in the APCP-induced anti-tumor immune response.

Insight into adenosine pathway in psoriasis: Elucidating its role and the potential therapeutical applications.

Psoriasis is an inflammatory skin disease, that can manifest as different phenotypes, however its most common form is psoriasis vulgaris (plaque psoriasis), characterized by abnormal keratinocyte proliferation, leading to characteristic histopathological signs of acanthosis, hyperkeratosis and parakeratosis. For many years, there has been a debate regarding whether keratinocyte dysfunction leads to immune system dysregulation in psoriasis or vice versa. It is now understood that epidermal hyperplasia results from immune system activation. Besides epidermal hyperplasia, psoriatic skin shows leukocyte infiltration, evident angiogenesis in the papillary dermis, characterized by tortuous, dilated capillaries, as well as oedema. There is substantial early evidence that adenosine is a key mediator of the immune response; it derives from ATP hydrolysis and accumulates into tissue in response to systemic and local stress conditions, hypoxia, metabolic stress, inflammation. Adenosine controls several cell functions by signalling through its 4 receptor subtypes, A1, A2A, A2B and A3. Evidence suggests that adenosine may play a role in psoriasis pathogenesis by controlling several immune cell functions, keratinocyte proliferation, neo-angiogenesis. Expression of adenosine receptor varies in psoriatic skin, and this can significantly impact on tissue homeostasis. Indeed, an altered adenosine receptor profile may contribute to the dysregulation observed in psoriasis, affecting immune responses and inflammatory pathways. Here, we discuss the role of adenosine in regulating the functions of the main cell populations implied in the pathogenesis of psoriasis. Furthermore, we give evidence for adenosine signalling pathway as target for therapeutic intervention in psoriasis.

High levels of soluble CD73 unveil resistance to BRAF inhibitors in melanoma cells.

Melanoma cells express high levels of CD73 that produce extracellular immunosuppressive adenosine. Changes in the CD73 expression occur in response to tumor environmental factors, contributing to tumor phenotype plasticity and therapeutic resistance. Previously, we have observed that CD73 expression can be up-regulated on the surface of melanoma cells in response to nutritional stress. Here, we explore the mechanism by which melanoma cells release soluble CD73 under low nutrient availability and whether this might be affected by agents targeting the proto-oncogene B-Raf (BRAF). We found that starved melanoma cells can release high levels of CD73, able to convert AMP into adenosine, and this activity is abrogated by selective CD73 inhibitors, APCP or PSB-12489. The release of CD73 from melanoma cells is mediated by the matrix metalloproteinase MMP-9. Indeed, MMP-9 inhibitors significantly reduce the levels of CD73 released from the cells, while its surface levels increase. Of relevance, melanoma cells, harboring an activating BRAF mutation, upon treatment with dabrafenib or vemurafenib, show a strong reduction of CD73 cell expression and reduced levels of CD73 released into the extracellular space. Conversely, melanoma cells resistant to dabrafenib show high expression of membrane-bound CD73 and soluble CD73 released into the culture medium. In summary, our data indicate that CD73 is released from melanoma cells. The expression of CD73 is associated with response to BRAF inhibitors. Melanoma cells developing resistance to dabrafenib show increased expression of CD73, including soluble CD73 released from cells, suggesting that CD73 is involved in acquiring resistance to treatment.

Drugs targeting adenosine signaling pathways: A current view.

Adenosine is an endogenous nucleoside that regulates many physiological and pathological processes. It is derived from either the intracellular or extracellular dephosphorylation of adenosine triphosphate and interacts with cell-surface G-protein-coupled receptors. Adenosine plays a substantial role in protecting against cell damage in areas of increased tissue metabolism and preventing organ dysfunction in pathological states. Targeting adenosine metabolism and receptor signaling may be an effective therapeutic approach for human diseases, including cardiovascular and central nervous system disorders, rheumatoid arthritis, asthma, renal diseases, and cancer. Several lines of evidence have shown that many drugs exert their beneficial effects by modulating adenosine signaling pathways but this knowledge urgently needs to be summarized, and most importantly, actualized. The present review collects pharmaceuticals and pharmacological or diagnostic tools that target adenosine signaling in their primary or secondary mode of action. We overviewed FDA-approved drugs as well as those currently being studied in clinical trials. Among them are already used in clinic A2A adenosine receptor modulators like istradefylline or regadenoson, but also plenty of anti-platelet, anti-inflammatory, or immunosuppressive, and anti-cancer drugs. On the other hand, we investigated dozens of specific adenosine pathway regulators that are tested in clinical trials to treat human infectious and noninfectious diseases. In conclusion, targeting purinergic signaling represents a great therapeutic challenge. The actual knowledge of the involvement of adenosinergic signaling as part of the mechanism of action of old drugs has open a path not only for drug-repurposing but also for new therapeutic strategies.

Lack of Ecto-5'-Nucleotidase Protects Sensitized Mice against Allergen Challenge.

Ecto-5'-nucleotidase (CD73), the ectoenzyme that together with CD39 is responsible for extracellular ATP hydrolysis and adenosine accumulation, regulates immune/inflammatory processes by controlling innate and acquired immunity cell functions. We previously demonstrated that CD73 is required for the assessment of a controlled allergic sensitization, in mice. Here, we evaluated the response to aerosolized allergen of female-sensitized mice lacking CD73 in comparison with their wild type counterpart. Results obtained show, in mice lacking CD73, the absence of airway hyperreactivity in response to an allergen challenge, paralleled by reduced airway CD23+B cells and IL4+T cells pulmonary accumulation together with reduced mast cells accumulation and degranulation. Our findings indicate CD73 as a potential therapeutic target for allergic asthma.

IL-17A increases ADP-induced platelet aggregation.

The increased risk of thromboembolism and higher incidence of cardiovascular disorders are among the most common causes of morbidity in patients suffering from autoimmune diseases. In this study we tested the hypothesis that IL-17A, a key pro-inflammatory cytokine involved in the development of autoimmune diseases, exerts pro-aggregant effects on both human and mouse platelets. Human or murine platelets were incubated with IL-17A for 2 min at 37°C prior the addition of the stimuli. Aggregation was monitored in a light transmission aggregometer measuring changes in turbidity with continuous observation over a 5-min interval after the addition of the stimuli. IL-17RA, CD42b and CD62P expression as well as fibrinogen bindings were measured by FACS while Erk-2 phosphorylation was analyzed by western blot using phospho-specific antibodies. Pre-incubation with IL-17A increased ADP-, but not collagen-induced platelet aggregation and accelerated CD62P expression and exposure of fibrinogen binding sites. These effects were associated with a faster kinetic of ADP-induced Erk-2 phosphorylation and were lost in platelets deficient in the IL-17 receptor. Together these results unveil a novel aspect of the inflammatory nature of IL-17A suggesting, at the same time, that therapeutic strategies targeting this cytokine might provide further benefit for the treatment of autoimmune diseases by reducing the risk of cardiovascular-related pathologies.

Thrombo-Inflammation: A Focus on NTPDase1/CD39.

There is increasing evidence for a link between inflammation and thrombosis. Following tissue injury, vascular endothelium becomes activated, losing its antithrombotic properties whereas inflammatory mediators build up a prothrombotic environment. Platelets are the first elements to be activated following endothelial damage; they participate in physiological haemostasis, but also in inflammatory and thrombotic events occurring in an injured tissue. While physiological haemostasis develops rapidly to prevent excessive blood loss in the endothelium activated by inflammation, hypoxia or by altered blood flow, thrombosis develops slowly. Activated platelets release the content of their granules, including ATP and ADP released from their dense granules. Ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1)/CD39 dephosphorylates ATP to ADP and to AMP, which in turn, is hydrolysed to adenosine by ecto-5'-nucleotidase (CD73). NTPDase1/CD39 has emerged has an important molecule in the vasculature and on platelet surfaces; it limits thrombotic events and contributes to maintain the antithrombotic properties of endothelium. The aim of the present review is to provide an overview of platelets as cellular elements interfacing haemostasis and inflammation, with a particular focus on the emerging role of NTPDase1/CD39 in controlling both processes.

Protective effect of dimethyl sulfoxide on acute myocardial infarction in rats.

Dimethyl sulfoxide (DMSO) is an organic compound widely used as solvent in biological studies and as vehicle for drug administration. DMSO has been shown to possess several biological effects, including antioxidant, anti-inflammatory, antinociceptive effects, and it has been proposed to be therapeutic in several disorders, such as gastrointestinal diseases, rheumatologic diseases, and for the treatment of several manifestations of amyloidosis. To better define the biological profile of DMSO, we investigated its effect on an in vivo model of acute myocardial infarction in rats, caused by left anterior descending coronary artery ligation. Our results show that pretreatment of rats with intraperitoneal (ip) DMSO (500 microL/Kg) for 3 consecutive days before left anterior descending coronary artery ligation significantly (P < 0.05) reduced cardiac damage from 18.75 +/- 4.88% (n = 12) to 4.46 +/- 2.01% (n = 8); serum levels of troponin I from 29.35 +/- 12.32 ng/mL (n = 8) to 2.95 +/- 1.32 ng/mL (n = 4); and serum levels of myoglobin from 46.86 +/- 10.35 ng/mL (n = 7) to 13.75 +/- 0.85 ng/mL (n = 4). Our data demonstrate that DMSO has a protective effect in a model of acute myocardial infarction in rats.

L-cysteine/cystathionine-ß-synthase-induced relaxation in mouse aorta involves a L-serine/sphingosine-1-phosphate/NO pathway.

BACKGROUND AND PURPOSE: Among the three enzymes involved in the transsulfuration pathway, only cystathionine ß-synthase (CBS) converts L-cysteine into L-serine and H2 S. L-serine is also involved in the de novo sphingolipid biosynthesis through a condensation with palmitoyl-CoA by the action of serine palmitoyltransferase (SPT). Here, we have investigated if L-serine contributes to the vasorelaxant effect. EXPERIMENTAL APPROACH: The presence of CBS in mouse vascular endothelium was assessed by immunohistochemistry and immunofluorescence. The relaxant activity of L-serine (0.1-300 µM) and L-cysteine (0.1-300 µM) was estimated on mouse aorta rings, with or without endothelium. A pharmacological modulation study evaluated NO and sphingosine-1-phosphate (S1P) involvement. Levels of NO and S1P were also measured following incubation of aorta tissue with either L-serine (1, 10, and 100 µM) or L-cysteine (10, 100 µM, and 1 mM). KEY RESULTS: L-serine relaxed aorta rings in an endothelium-dependent manner. The vascular effect was reduced by L-NG-nitro-arginine methyl ester and wortmaninn. A similar pattern was obtained with L-cysteine. The S1P1 receptor antagonist (W146) or the SPT inhibitor (myriocin) reduced either L-serine or L-cysteine relaxant effect. L-serine or L-cysteine incubation increased NO and S1P levels in mouse aorta. CONCLUSIONS AND IMPLICATIONS: L-serine, a by-product formed within the transsulfuration pathway starting from L-cysteine via CBS, contributes to the vasodilator action of L-cysteine. The L-serine effect involves both NO and S1P. This mechanism could be involved in the marked dysregulation of vascular tone in hyperhomocysteinemic patients (CBS deficiency) and may represent a feasible therapeutic target. LINKED ARTICLES: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.

Exacerbation of Allergic Airway Inflammation in Mice Lacking ECTO-5'-Nucleotidase (CD73).

The airways are a target tissue of type I allergies and atopy is the main etiological factor of bronchial asthma. A predisposition to allergy and individual response to allergens are dependent upon environmental and host factors. Early studies performed to clarify the role of extracellular adenosine in the airways highlighted the importance of adenosine-generating enzymes CD73, together with CD39, as an innate protection system against lung injury. In experimental animals, deletion of CD73 has been associated with immune and autoimmune diseases. Our experiments have been performed to investigate the role of CD73 in the assessment of allergic airway inflammation following sensitization. We found that in CD73-/- mice sensitization, induced by subcutaneous ovalbumin (OVA) administration, increased signs of airway inflammation and atopy developed, characterized by high IgE plasma levels and increased pulmonary cytokines, reduced frequency of lung CD4+CD25+Foxp3+ T cells, but without bronchial hyperreactivity, compared to sensitized wild type mice. Our results provide evidence that the lack of CD73 causes an uncontrolled allergic sensitization, suggesting that CD73 is a key molecule at the interface between innate and adaptive immune response. The knowledge of host immune factors controlling allergic sensitization is of crucial importance and might help to find preventive interventions that could act before an allergy develops.

The relatively selective cyclooxygenase-2 inhibitor nimesulide: What's going on?

Nimesulide is a relatively selective cyclooxygenase (COX)-2 inhibitor, non-steroidal anti-inflammatory drug; it has been discovered in 1971 and firstly commercialized in Italy in 1985. There is much evidence that the pharmacological profile of nimesulide is peculiar and not shared with the other COX-2 selective inhibitors, suggesting that other molecular mechanisms besides inhibition of COX-2 derived prostaglandins are involved. Similarly, experimental data suggest that the gastrointestinal safety of nimesulide cannot be ascribed only to a COX-1 sparing effect. On the inflammatory process, the efficacy of nimesulide is dependent upon a wide spectrum of actions, due to the combination of effects on immune and non-immune cells. Early data demonstrated a central role for cyclic AMP (cAMP) in the anti-inflammatory effect of nimesulide; more recently, we have shown the involvement of the pathway ecto-5'-nucleotidase/adenosine A2A receptor. To date, the molecular mechanism(s) that confers uniqueness to nimesulide have not yet been defined. To go inside the mechanism of action of an existing drug, such as nimesulide, would be helpful to refine its therapeutic use but also to identify new targets for novel therapeutic anti-inflammatory approach. Here, we focus on accumulated evidence for a peculiar pharmacological profile of nimesulide.